Design, synthesis and anti-tuberculosis activity of 1-adamantyl-3- heteroaryl ureas with improved in vitro pharmacokinetic properties

E. Jeffrey North, Michael S. Scherman, David F. Bruhn, Jerrod S. Scarborough, Marcus M. Maddox, Victoria Jones, Anna Grzegorzewicz, Lei Yang, Tamara Hess, Christophe Morisseau, Mary Jackson, Michael R. McNeil, Richard E. Lee

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45 Scopus citations

Abstract

Out of the prominent global ailments, tuberculosis (TB) is still one of the leading causes of death worldwide due to infectious disease. Development of new drugs that shorten the current tuberculosis treatment time and have activity against drug resistant strains is of utmost importance. Towards these goals we have focused our efforts on developing novel anti-TB compounds with the general structure of 1-adamantyl-3-phenyl urea. This series is active against Mycobacteria and previous lead compounds were found to inhibit the membrane transporter MmpL3, the protein responsible for mycolic acid transport across the plasma membrane. However, these compounds suffered from poor in vitro pharmacokinetic (PK) profiles and they have a similar structure/SAR to inhibitors of human soluble epoxide hydrolase (sEH) enzymes. Therefore, in this study the further optimization of this compound class was driven by three factors: (1) to increase selectivity for anti-TB activity over human sEH activity, (2) to optimize PK profiles including solubility and (3) to maintain target inhibition. A new series of 1-adamantyl-3-heteroaryl ureas was designed and synthesized replacing the phenyl substituent of the original series with pyridines, pyrimidines, triazines, oxazoles, isoxazoles, oxadiazoles and pyrazoles. This study produced lead isoxazole, oxadiazole and pyrazole substituted adamantyl ureas with improved in vitro PK profiles, increased selectivity and good anti-TB potencies with sub μg/mL minimum inhibitory concentrations.

Original languageEnglish (US)
Pages (from-to)2587-2599
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume21
Issue number9
DOIs
StatePublished - May 1 2013

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Keywords

  • Antibiotics
  • Antimicrobial agents
  • Medicinal chemistry
  • MmpL3
  • Transporter
  • Tuberculosis

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

North, E. J., Scherman, M. S., Bruhn, D. F., Scarborough, J. S., Maddox, M. M., Jones, V., Grzegorzewicz, A., Yang, L., Hess, T., Morisseau, C., Jackson, M., McNeil, M. R., & Lee, R. E. (2013). Design, synthesis and anti-tuberculosis activity of 1-adamantyl-3- heteroaryl ureas with improved in vitro pharmacokinetic properties. Bioorganic and Medicinal Chemistry, 21(9), 2587-2599. https://doi.org/10.1016/j.bmc.2013.02.028